The Retroviral Diseases Section of the HIV and AIDS Malignancy Branch conducts translational clinical and laboratory research aimed at the development of novel therapies for HIV infection and AIDS- related malignancies. It also conducts laboratory research focused on an understanding of these diseases. During the past year, the group has investigated the role of conserved cysteines at positions 67 and 95 on the activity of HIV protease. We have previously found that glutathiolation of Cys 95 (in the dimer interface) abolishes HIV-1 protease activity, while glutathiolation of Cys 67 can enhance activity. HIV virions with mutations of Cys 95 and Cys67 have been generated and we are studying the effects that these mutations have on the fitness of HIV under varying conditions. We have recently found that nearly all retroviral proteases are regulated by oxidizable amino acids at the dimer interface and that in the case of HIV-1, this occurs by interfering with dimer formation. HIV from some patients who have developed resistance to protease inhibitors have been also found to develop a mutation in Cys95, and we are trying to understand the evolutionary pressures leading to this mutation. This work on HIV protease has identified the dimer interface as a potential therapeutic target, and we are attempting to design inhibitors of HIV protease that act as this site. We are also investigating the role of a newly discovered herpes virus, called Kaposi's sarcoma-associated herpes virus (KSHV) or human herpesvirus-8 (HHV-8), in the pathogenesis of Kaposi's sarcoma (KS). We have found that hypoxia can activate latent KSHV to undergo lytic replication. We have found evidence that three genes of KSHV are specifically upregulated by hypoxia: Rta, ORF34, and viral Bcl-2. ORF34 is part of a cluster of genes (ORF34 to 37), and we are currently analyzing this cluster and their regulation by hypoxia. One of these genes, ORF36, can phosphorylate ganciclovir, and activation of this gene by hypoxia may be able to be used to therapeutic benefit in KSHV-associated tumors, especially PEL. We are also conducting several clinical trials to evaluate novel therapies for Kaposi's sarcoma with a focus on anti-angiogenesis approaches. We have found preliminary evidence that the cytokine IL-12 has long-acting activity in Kaposi's sarcoma have initiated a trial to study the combination of IL-12 and a liposomal anthracycline in patients with advanced KS. We are also studying antibody to VEGF as a therapeutic agent in KS. We are initiating a natural history study of multicentric Castleman's disease (MCD), which is also caused by KSHV and plan to explore a therapeutic strategy involving antiviral rugs activated by KSHV. We are also studying infusional chemotherapy as therapy for AIDS-associated lymphoma in collaboration with the Experimental Immunology and Transplantation Branch. In regard to anti-HIV therapy, we are initiating a clinical trial to explore whether specific immunity can be developed to a crucial sequence in reverse transcriptase. 100% AIDS related.